This invention relates to a dialysis membrane for hemodialysis in the form of sheet films, tubular films, or hollow fibers composed of polysaccharide ether.
There are very high demands on dialysis membranes with regard to biocompatibility so that the blood flowing past the membranes is damaged as little as possible. Important parameters of biocompatibility are thrombogenicity, leukopenia, and complement activation.
DE-OS 35 24 596 discloses a dialysis membrane with improved biocompatibility that is able to reduce leukopenia and complement activation to a considerable extent and that is distinguished by modified cellulose whose average degree of substitution is 0.02 to 0.07. The known dialysis membrane composed of modified cellulose preferably contains modified cellulose that has a structure given by the formula EQU Cellulose-R'--X--Y
in which
X stands for --NR"-- and/or ##STR2## and/or --S-- and/or --SO-- and/or --SO.sub.2 -- and/or ##STR3## and/or --CO--O-- and/or --O-- Y stands for --R and/or --NR.sub.2 and/or --Si(OR").sub.3 and/or --SO.sub.3 H and/or --COOH and/or --PO.sub.3 H.sub.2 and/or ##STR4## and their salts, R' stands for an alkylene group and/or a cycloalkylene group and/or an arylene group with a total of 1 to 25 carbon atoms, PA1 R" stands for a hydrogen atom or R, and PA1 R stands for an alkyl group with 1 to 5 carbon atoms and/or a cycloalkyl group and/or an aryl group.
However, these membranes show elevated thrombogenicity compared to conventional dialysis membranes, such as Cuprophan.RTM., for example, especially when the substituent is an ionic group, but above all when the substituent is a basic group.
Furthermore, EP-A-0 459 293 discloses a dialysis membrane for hemodialysis in the form of sheet films, tubular films, or hollow fibers composed of polysaccharide ethers. The polysaccharide ethers have a structure given by the formula ##STR5## wherein cell is the skeleton of the unmodified cellulose molecule or of the chitin molecule, with no hydroxyl groups in each case, s is equal to 3 for the unmodified cellulose molecule and 2 for the chitin molecule, and x stands for the degree of etherification, which is in the range of 0.08 to (s-0.4), and wherein R is an optionally substituted alkyl, alkenyl and/or alkynyl and/or cycloalkyl and/or cycloalkenyl and/or cycloalkynyl and/or arylalkyl and/or arylalkenyl and/or arylalkynyl and/or bisarylalkyl and/or bisarylalkenyl and/or bisarylalkynyl group with 5 to 40 carbon atoms, and/or the radical of a condensed aromatic (optionally substituted) compound and/or the radical of a heterocyclic (optionally substituted) compound.
The polysaccharide is relatively highly substituted and also contains ionic groups, which likewise increase the thrombogenicity.
Dialysis membranes composed of synthetic or natural polymers can very easily cause clotting of the blood when they are used in artificial kidneys, which is prevented to a great extent by appropriate drug treatment. In addition, however, when a patient receives dialysis treatment with dialyzers that contain membranes composed of regenerated cellulose, a temporary decrease of leukocytes occurs in the initial period of dialysis treatment. This effect is called leukopenia.
Leukopenia is a lowering of the leukocyte count (white blood cells) in the circulatory system. The number of white blood cells in humans is about 4000 to 12,000 cells/mm.sup.3. Leukopenia in dialysis is most severe 15 to 20 minutes after the beginning of treatment, during which the neutrophils (leukocytes that can be stained with neutral dyes or at the same time with acidic and basic dyes) may disappear almost completely. The number of leukocytes then recovers to almost the initial value within about an hour, or exceeds it. If a new dialyzer is connected after the recovery of the leukocytes, leukopenia occurs again to the same extent.
Cellulose membranes cause pronounced leukopenia. Although the clinical significance of leukopenia is not scientifically clear, there is nevertheless a desire for a dialysis membrane for hemodialysis that does not show the effect of leukopenia, without impairing the desired positive characteristics of dialysis membranes composed of regenerated cellulose.
Distinct complement activation has been found in addition to leukopenia during hemodialysis with membranes composed of regenerated cellulose. The complement system in the blood serum is a complex plasma enzyme system consisting of many components that serves in various ways as a defense against damage from invading foreign cells (bacteria etc.). If antibodies against the invading organism are present, complement-specific activation can occur from the complex of the antibodies with antigenic structures of the foreign cells; otherwise complement activation occurs on an alternate pathway through distinctive surface features of the foreign cells. The complement system depends on a number of plasma proteins. After activation, these proteins react specifically with one another in a definite sequence, and at the end a cell-damaging complex is formed that destroys the foreign cells.
Peptides are liberated from individual components that trigger inflammatory symptoms and sometimes also may have adverse pathological consequences for the body. It is assumed that activation with hemodialysis membranes composed of regenerated cellulose occurs over the alternate pathway. These complement activations are identified objectively by determination of the complement fragments C3a and C5a.
Reference is made in this regard to the following papers: D. E. Chenoweth et al., Kidney International Vol. 24, pages 764 ff, 1983, and D. E. Chenoweth, Asaio-Journal Vol. 7, pages 44 ff, 1984.
It is also desirable to prevent thrombogenicity and the heparin absorption that occurs to a substantial extent particularly with the polysaccharide ethers pursuant to DE-OS 35 24 596. A reusable dialysis membrane composed of polysaccharide ethers with an even lower degree of modification than that described in EP-A-0 459 293 is also desirable to reduce costs.
However, in the procedures used up to now to prepare for reuse, precisely the parameter critical for biocompatibility is distinctly impaired, and steam sterilization leads to yellowing of the membranes.
Although dialysis membranes composed of polysaccharide ether with usable biocompatibility characteristics are already known, there is a need to improve them further.